Oligodendrocyte Progenitors and Mechanisms of Human Vascular White Matter Injury

少突胶质细胞祖细胞和人类血管白质损伤的机制

基本信息

批准号：
10618140
负责人：
Stephen Arthur Back
金额：
$ 67.78万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618140
关键词：
3-nitrotyrosine Abbreviations Acetylcholine Acids Adhesions Adult Age Years Aging Autopsy Biology Blood Vessels Blood capillaries Blood flow Brain CD44 gene Catabolism Cell Maturation Cerebral Ischemia Cerebrovascular Trauma Cerebrum Cholinergic Agonists Chronic Clinical Cognitive Collection Data Dementia Diameter Diffuse Elderly Endothelial Cells Endothelium Extracellular Matrix Extravasation Failure Fibrinogen Functional disorder Genes Human Hyaluronic Acid Impaired cognition Impairment Individual Inflammation Inflammatory Injury Isoprostanes Lesion Leukocytes Link Lymphocyte Magnetic Resonance Imaging Measures Mediating Microvascular Dysfunction Molecular Mus Muscarinic Acetylcholine Receptor Myelin Natural regeneration Nitric Oxide Nitrogen Oligodendroglia Oxidative Stress Oxygen Pathogenesis Pathologic Patients Penetration Peroxides Physiology Play Predisposition Process Production Proliferating Recovery Risk Role Site Superoxides Surface Techniques Testing Vascular Cognitive Impairment Vascular Dementia Vascular Diseases Vascular Endothelium Vascular Permeabilities Vasodilation Vasodilator Agents White Matter Hyperintensity aging brain arteriole brain cell cell motility cell type cerebrovascular cholinergic clinical predictors cohort dementia risk endothelial dysfunction ex vivo perfusion gray matter in vitro Model migration mouse model multidisciplinary myelination neuroimaging neuropathology nitrosative stress nonhuman primate novel oligodendrocyte progenitor overexpression oxidative damage remyelination repaired response response to injury shear stress stem cell proliferation stem cells therapy development vascular cognitive impairment and dementia vascular factor vascular inflammation vascular injury white matter white matter injury

项目摘要

Project Summary Progress to define mechanisms of white matter injury (WMI) in vascular cognitive impairment and dementia (VCID) has been hampered by fundamental gaps in our understanding of the vascular and glial mechanisms related to the pathogenesis of remyelination failure, a hallmark of VCID. We propose a highly integrated analysis of the interplay between microvascular and oligodendrocyte progenitor cell (OPC) contributions to VCID pathogenesis. We will mechanistically link dysfunctional reactivity and inflammation of the WM vasculature to novel perivascular disturbances in OPC responses to WMI that appear central to myelination failure in VCID. We will test the over-riding hypothesis that dysfunction of white matter arterioles establishes selectively vulnerable zones of perivascular WMI from oxidative and nitrosative stress that result in functionally dysmature white matter niches associated with aberrant OPC migration, proliferation and differentiation to myelinating oligodendrocytes. This hypothesis is supported by our recent studies (Bagi et al., Ann Neurol 2018; 83:142-152) that identified selectively impaired vasodilator function of human WM penetrating arterioles in microvascular brain injury (mVBI) in similar white matter regions where disrupted maturation of pre-myelinating OPCs occurred. In all three aims, we will employ a unique collection of human rapid autopsy brains from a large cohort of cases with VCID where white matter hyperintensities (WMHs) were identified by ante-mortem MRI. Although WMHs are widely used clinically to identify patients at risk for cognitive decline, their pathological basis is poorly defined. In aim 1, we will define mechanistic relationships among impaired cholinergic vasodilation of white matter arterioles, high vascular wall shear stress and WMI arising from augmented production of reactive oxygen and nitrogen species. We will test the hypothesis that impaired cholinergic vasodilation exposes endothelial cells in WM penetrating arterioles to a high level of wall shear stress, which induces augmented production of reactive oxygen and nitrogen species in mVBI. In aim 2, we will define molecular disturbances in the OPC-vascular niche that contribute to myelination failure in mVBI. We will focus on the role of vascular factors in aberrant OPC migration, proliferation and maturation. We will capitalize on several new lines of data that demonstrate novel perivascular injury responses of OPCs at the level of WM arterioles and capillaries. In aim 3, we will define vascular extracellular matrix mechanisms related to hyaluronic acid (HA)-mediated dysfunction of WM arterioles. We will integrate approaches using murine and human vessels to define the role of various forms of HA in vascular inflammation, loss of vascular integrity and abnormal leukocyte adhesion and extravasation across the vascular endothelium. Our over-riding objective is to provide a mechanistic molecular explanation for the distinct OPC-vascular processes that render aging human white matter particularly susceptible to microvascular WMI in order to develop therapies that promote remyelination in chronic WMI.

项目摘要在血管认知障碍和痴呆症中定义白质损伤机制（WMI）的进展（VCID）在我们对血管和神经胶质机制的理解中受到了基本差距的阻碍与VCID的标志性雷梅拉尔失败的发病机理有关。我们提出了一个高度整合的分析微血管和少突胶质细胞祖细胞（OPC）贡献对 VCID发病机理。我们将机械地连接功能障碍的反应性和WM的炎症 OPC对WMI的新型周围血管障碍的脉管系统似乎是髓鞘的核心 VCID失败。我们将测试白质小动脉功能障碍的过度骑行假设通过氧化和亚硝化应激，建立有选择性的脆弱区域WMI区域导致功能障碍的白质壁ni与异常的OPC迁移相关的壁chi，增殖和与髓生成少突胶质细胞的分化。这个假设得到了我们的支持最近的研究（Bagi等，Ann Neurol 2018; 83：142-152），鉴定出有选择性损害的血管扩张剂人类WM穿透动脉在微血管脑损伤（MVBI）中的功能在类似的白质中的功能发生了破坏前疗程OPC成熟的区域。在这三个目标中，我们将采用从大量的vCID案例中，人类快速尸检大脑的独特集合，白质通过前验证MRI鉴定高强度（WMH）。尽管WMH在临床上被广泛使用确定有认知能力下降的患者，其病理基础的定义很差。在AIM 1中，我们将定义白质小动脉胆碱能血管舒张受损，高血管壁之间的关系剪切应力和WMI是由活性氧和氮种的增加产生的。我们将测试胆碱能血管舒张受损的假设使WM穿透动脉中的内皮细胞暴露于高水平的壁剪应力，可诱导活性氧和氮的产生在MVBI。在AIM 2中，我们将定义OPC血管生态位的分子障碍，这有助于 MVBI中的髓鞘衰竭。我们将重点介绍血管因素在异常OPC迁移中的作用，增殖和成熟。我们将利用几条新的数据，这些数据展示了新颖的数据 OPC在WM动脉和毛细血管水平上的血管周期损伤反应。在AIM 3中，我们将定义与透明质酸（HA）介导的WM功能障碍有关的血管外基质机制小动脉。我们将使用鼠和人类船只来整合方法，以定义各种形式的作用 HA在血管炎症中，血管完整性的丧失和异常白细胞粘附和渗出穿过血管内皮。我们的过度目标是提供机械性分子解释对于不同的OPC血管过程，使衰老的人类白质特别容易受到影响微血管WMI是为了开发促进慢性WMI延期性的疗法。